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  • Brain-derived neurotrophic factor (BDNF) enhances the function and survival of nerve cells. Glucocorticoids decrease the production of BDNF. Stress increases the release of glucocorticoids, leading to decreased neuronal function and survival, particularly in the hippocampus. Glucocorticoids also cause the hippocampus to inhibit CRF release, thereby decreasing the release of glucocorticoids. In this way the effects of glucocorticoids on neuronal function and survival are controlled.
  • People who are susceptible to depression often become depressed after experiencing stress. This susceptibility may be due to genetic factors and/or previous neuronal injury (e.g. stroke). Depressed patients tend to have elevated glucocorticoid levels in the bloodstream, possibly due to an impairment of the ability of the hippocampus to inhibit CRF release. Elevated glucocorticoid levels decrease BDNF release, leading to neuronal atrophy in the hippocampus and other brain areas. Atrophy of hippocampal neurons further impairs the ability to inhibit CRF release, leading to a further increase in glucocorticoids, leading to further neuronal atrophy, etc. It is proposed that depression results from neuronal atrophy in the hippocampus and other brain areas (e.g. prefrontal cortex), and/or altered neural activity in cortical areas that are influenced by the hippocampus.
  • Antidepressants increase the activity of the cAMP signal transduction system (and possibly other signal transduction systems) by increasing synaptic NE and 5-HT and by other, less well understood mechanisms. This leads to increased BDNF release, resulting in enhanced growth and function of neurons. The ability of the hippocampus to inhibit CRF release is restored, and glucocorticoid levels are controlled.
  • pharmacologyofantidepressa.ppt

    1. 1. “Pharmacology of antidepressants” Objectives 1. Know the different classes of antidepressant 4. Know the factors that influence the choice of antidepressant 2. Know the main subtypes of depressive disorder 3. Know the diagnostic criteria for depression 5. Know the basics of depression etiology
    2. 2. “Pharmacology of antidepressants” Objectives 9. Know the neurotrophic hypothesis of depression and antidepressant action 6. Know the neuroanatomical features of depression 7 . Know the mechanisms of antidepressant drug action 8. Know the monoamine depletion hypothesis of depression
    3. 3. “Pharmacology of antidepressants” Overview Classification of antidepressant drugs What is depression? Factors affecting drug choice Mechanisms of antidepressant drug action Neuroanatomy of depression Hypotheses of depression
    4. 4. Currently available antidepressants Tricyclics Amitriptyline (Elavil) Desipramine (Norpramin) Imipramine (Tofranil) Nortriptyline (Pamelor)
    5. 5. Currently available antidepressants Monoamine oxidase inhibitors (MAOI) Phenelzine (Nardil) Tranylcypromine (Parnate) Moclobemide (Manerix)
    6. 6. Currently available antidepressants Selective serotonin reuptake inhibitors (SSRI) Citalopram (Celexa) Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Fluvoxamine (Luvox)
    7. 7. Currently available antidepressants Triazolopyridines Nefazodone (Serzone), Trazodone (Desyrel) Aminoketone - Bupropion (Wellbutrin) 5-HT/NE reuptake inhibitor - Venlafaxine (Effexor) Tetracyclic - Mirtazapine (Remeron) Other antidepressants
    8. 8. What is depression? Diagnostic criteria Neurochemical features Neuroanatomical features Subtypes of depression Etiology (causes)
    9. 9. Major depression Dysthymic disorder Melancholic depression Subtypes of depression Atypical depression Others, e.g. bipolar disorder (Dr. Filtz)
    10. 10. Features of melancholic depression Subtypes of depression Episodic Anhedonia (unable to cheer up) Anorexia, weight loss Insomnia Worse in the morning Tendency to respond preferentially to electroconvulsive therapy (ECT), TCAs and SSRIs
    11. 11. Features of atypical depression Subtypes of depression Chronic (not episodic) Can cheer up temporarily Overeating, weight gain Hypersomnia (sleep more) Worse in the evening Tendency to respond preferentially to MAOIs
    12. 12. Dysthymic disorder Subtypes of depression Persistent depression Milder than major depression Risk of developing into major depression Responsive to a variety of antidepressants
    13. 13. Subtypes of depression Main point: There are different subtypes of depressive disorder. The relative efficacy of different types of antidepressant can depend to an extent on the subtype of depression being treated
    14. 14. Diagnostic criteria for depression 1. Depressed mood most of the time 2. Markedly diminished pleasure in almost all activities 3. Significant weight loss or gain, or change in appetite 4. Insomnia or hypersomnia nearly every day 5. Psychomotor agitation or retardation nearly every day 6. Fatigue or loss of energy nearly every day 7. Feelings of worthlessness or guilt nearly every day 8. Diminished ability to concentrate or make decisions 9. Recurrent thoughts of death or suicide
    15. 15. Diagnostic criteria for depression Major depressive episode (melancholic or atypical) At least five symptoms, including #1 and/or #2 Dysthymic disorder At least three symptoms, including #1
    16. 16. Diagnostic criteria for depression Main point: The diagnosis of depression relies on interpretation of behavioral and subjective characteristics of the patient No lab tests available
    17. 17. Antidepressants – drug choice
    18. 18. Antidepressants – drug choice In general, antidepressants are equal in efficacy when administered in comparable doses Efficacy Individually, patients may respond to one type of antidepressant but not another type Differential responses in different subtypes of depression
    19. 19. Antidepressants – drug choice Treatment-resistant depression 40-50% of patients have inadequate response to an antidepressant Switch drugs – ensure washout before switching to/from MAOI Drug combinations: TCA + MAOI sometimes works, but combining MAOI with another antidepressant is risky. SSRI + MAOI combination is not used. Electroconvulsive therapy
    20. 20. Antidepressants – drug choice Augmentation Sometimes the antidepressant effect can be enhanced by combining the antidepressant with a non-antidepressant drug e.g. lithium liothyronine (synthetic thyroid hormone) anticonvulsants
    21. 21. Antidepressants – drug choice Adverse effects May vary between individuals
    22. 22. Antidepressants – drug choice Pre-existing medical conditions Cardiovascular disease – be careful with TCAs Neurological disease – consider seizure risk Obesity, anorexia – TCAs cause weight gain Interactions with other drugs
    23. 23. Antidepressants – drug choice Main point: Choice of antidepressant depends on individual efficacy and side effects, subtype of depressive disorder, pre- existing medical conditions and other drugs being taken.
    24. 24. Antidepressants – adverse effects
    25. 25. Antidepressants – adverse effects Tricyclic antidepressants - TCAs Muscarinic ACh antagonists: “anticholinergic” side effects e.g. dry mouth, blurred vision, constipation, urinary retention, tachycardia (high heart rate), memory impairment, sedation
    26. 26. Antidepressants – adverse effects Tricyclic antidepressants - TCAs Alpha1-adrenergic antagonists: Orthostatic hypotension with resultant syncope (fainting when you stand up because of a drop in blood pressure)
    27. 27. Antidepressants – adverse effects Tricyclic antidepressants - TCAs H-1 histaminergic antagonists: e.g. sedation, weight gain
    28. 28. Antidepressants – adverse effects Tricyclic antidepressants - TCAs Cardiac arrhythmia – abnormal heart rhythm (in high doses or with pre-existing heart disease)
    29. 29. Antidepressants – adverse effects Tricyclic antidepressants - TCAs Excessive perspiration, sexual dysfunction (may lead to noncompliance) Can cause seizures in some people
    30. 30. Antidepressants – adverse effects Monoamine oxidase inhibitors - MAOIs Anticholinergic (less severe than TCAs) Sedation (less severe than TCAs) Cardiac arrhythmia (less severe than TCAs)
    31. 31. Can cause seizures in some people Antidepressants – adverse effects Monoamine oxidase inhibitors - MAOIs Sexual dysfunction is common
    32. 32. Antidepressants – adverse effects Monoamine oxidase inhibitors - MAOIs Interact with certain foods to cause hypertensive crisis (dangerously high blood pressure) Some foods contain tyramine, which increases blood pressure, and is normally metabolized by MAO Aged cheeses, e.g. cheddar, blue cheese are particularly bad and should be avoided Wensleydale?
    33. 33. Antidepressants – adverse effects Monoamine oxidase inhibitors - MAOIs Interact with certain drugs to cause hypertensive crisis Drugs that increase synaptic monoamines and sympathomimetic drugs should be avoided Includes other antidepressants and over-the-counter flu medications
    34. 34. Antidepressants – adverse effects Selective serotonin reuptake inhibitors - SSRIs nausea vomiting diarrhea Sexual dysfunction headache insomniafatigue Can cause seizures in some people
    35. 35. Antidepressants – adverse effects Main points: TCAs have a lot of side effects MAOIs have dangerous food and drug interactions SSRIs are safer
    36. 36. How do antidepressants relieve depression?
    37. 37. Molecules (neurotransmitters, receptors, ion channels, transporters) neurons synapses Neural networks ? Higher cortical function (consciousness, cognition, mood) Drugs act here
    38. 38. Complex etiology Genetic component - Multiple genes Environmental component – stress, neuronal injury Etiology (causes) of depression
    39. 39. amygdala thalamus Prefrontal cortex hippocampus striatum Neural network of emotion (greatly simplified) Limbic System Neuroanatomy of depression hypothalamus
    40. 40. Neuroanatomy of depression Prefrontal cortex (PFC) Altered blood flow and metabolism in depression Increased in some parts of PFC; can be reversed with antidepressants Decreased in other parts of PFC
    41. 41. Decreased metabolism in prefrontal cortex in depression
    42. 42. Neuroanatomy of depression Amygdala and thalamus Increased blood flow and metabolism in depression Can be reversed with antidepressants
    43. 43. Striatum Neuroanatomy of depression Reduced blood flow and metabolism in caudate (part of striatum) Reduced size of caudate
    44. 44. Neuroanatomy of depression Hippocampus Stress causes atrophy of hippocampal neurons Hippocampal volume is decreased in depression
    45. 45. Neuroanatomy of depression Main point: Depression is often characterized by alterations of function and/or anatomy in brain areas that are involved in emotion. Some of these alterations are reversed by antidepressants.
    46. 46. Antidepressants - mechanisms of action
    47. 47. Antidepressants – mechanisms of action Tricyclics inhibit reuptake of norepinephrine and serotonin Monoamine oxidase inhibitors irreversibly inhibit MAO (moclobemide competitively inhibits MAOA subtype) Selective serotonin reuptake inhibitors inhibit SERT (serotonin transporter)
    48. 48. Triazolopyridines are 5-HT2A receptor antagonists and inhibit 5-HT reuptake Bupropion inhibits dopamine and norepinephrine reuptake venlafaxine inhibits reuptake of norepinephrine and serotonin Antidepressants – mechanisms of action Mirtazapine: antagonist of alpha-2 adrenergic autoreceptors and heteroreceptors; effect is increased NE and 5-HT activity
    49. 49. Antidepressants – mechanisms of action postsynaptic 5-HT15-HT2A 5-HT3-7 5-HT 5-HT1A,1D SERT 5-HT MAO X MAOI X SSRI, TCA, Triazolopyridines Serotonergic effects Alpha2 AR Inhibitory heteroreceptor Inhibitory autoreceptors presynaptic 5-HT transporter Mirtazapine X Triazolopyridines X
    50. 50. Antidepressants – mechanisms of action postsynaptic Beta2 AR NE Alpha2 AR NET NE MAO X MAOI X TCA Noradrenergic effects Beta1 AR Alpha2 AR 5-HT1D,2A Inhibitory heteroreceptors Inhibitory autoreceptor presynaptic NE transporter Mirtazapine X
    51. 51. Monoamine depletion hypothesis: Depression results from reduced availability of 5-HT and/or NE
    52. 52. The monoamine depletion hypothesis predicts that depletion of monoamines causes depression However… Depletion of NE by inhibition of tyrosine hydroxylase or depletion of 5-HT by tryptophan-free diet does not cause depression in normal individuals
    53. 53. Patients with depression taking NE selective reuptake inhibitors become depressed if their NE is depleted Patients with depression taking 5-HT selective reuptake inhibitors become depressed if their 5-HT is depleted But…
    54. 54. 5-HT and NE seem to be required for the maintenance of the antidepressant response Main point: Monoamine depletion alone is not sufficient to cause depression
    55. 55. Antidepressants take 2-4 weeks to reach maximum effect. How is this related to their mechanism of action?
    56. 56. 5-HT(-) (+) Postsynaptic response No drug Acute antidepressant (several days) Chronic antidepressant (4 weeks) 5-HT (+) 5-HT (+) down-regulation of presynaptic 5-HT1A autoreceptors down-regulated 5-HT1A Bigger response (-) (-) 5-HT1A
    57. 57. 1 2 3 4 Weeks of antidepressant treatment Antidepressant effect Pindolol: 5-HT1A autoreceptor antagonist Expected effect of pindolol Observed effect of pindolol
    58. 58. Main point: The 2-4 week delay in antidepressant action can be partly (but not completely) explained by down-regulation of presynaptic 5-HT1A inhibitory autoreceptors.
    59. 59. Neurotrophic hypothesis of depression
    60. 60. Beta adrenergic 5-HT4,6,7 Gs Gs nucleus Adenylyl Cyclase cAMP Protein kinase A CREB BDNF Increased function and survival of neurons = up-regulated by antidepressants Antidepressant effect
    61. 61. Chronic antidepressant treatment results in sustained activation of the cAMP second messenger system, leading to up-regulation of brain-derived neurotrophic factor (BDNF). Main point: (other second messenger systems may also be involved)
    62. 62. Hippocampus hypothalamus pituitary adrenal CRF ACTH (-) glucocorticoids Xdepression Other brain areas CRF (increased by stress) (-) (-)
    63. 63. Release of corticotropin releasing factor (CRF) by the hypothalamus is increased in depressed patients Main point:
    64. 64. Neurotrophic hypothesis of depression neuronal function and survival Stress glucocorticoids BDNF (+) (+) (-) (-) CRF (-) (+) (+) hippocampus other brain regions (+) Normal state
    65. 65. Neurotrophic hypothesis of depression Stress glucocorticoids BDNF (+) (-) CRF (-) (+) Depressed state (-) (+) neuronal function and survival hippocampus other brain regions (+) (+)
    66. 66. antidepressants NE, 5-HT Neurotrophic hypothesis of depression Stress glucocorticoids BDNF (+) (-) CRF (-) (+) cAMP(+) (+) (+) (+) neuronal function and survival hippocampus other brain regions (+) (-) (+) (+)
    67. 67. Neurotrophic hypothesis of depression Main point: In susceptible individuals (genetic factors or pre-existing injury) stress causes impaired function and/or atrophy of hippocampal neurons (via inhibition of BDNF release by glucocorticoids). This decreases the ability of the hippocampus to inhibit the release of CRF by the hypothalamus, leading to increased glucocorticoid release. A cycle of CRF disinhibition and atrophy ensues. Altered function and/or atrophy may also occur in other brain areas, via hippocampal connections and/or glucocorticoid/BDNF action.
    68. 68. Neurotrophic hypothesis of depression Main point: By increasing monoamine levels and stimulating the cAMP second messenger pathway (and possibly other pathways), antidepressants stimulate the release of BDNF, which reverses the neuronal atrophy and restores neuronal function.
    69. 69. “Pharmacology of antidepressants” The Main Points again Depression is a disease that has many subtypes Diagnosis is dependent upon patient interviews and observation of behavior There are no laboratory tests for depression Antidepressants alter NE and 5-HT neurotransmission. Neurotrophic hypothesis Monoamine depletion hypothesis